Association of First-Trimester Low PAPP-A Levels (<0.2 MoM) with Maternal and Fetal Outcomes
##plugins.themes.bootstrap3.article.main##
Background and Aim: First-trimester screening is routinely performed globally to detect chromosomal abnormalities using non-invasive methods such as nuchal translucency (NT) measurements, pregnancy-associated plasma protein A (PAPP-A), and β-human chorionic gonadotropin (β-hCG). Recent studies have highlighted that low PAPP-A levels may be associated with adverse pregnancy outcomes, including pre-eclampsia, intrauterine growth restriction (IUGR), and pre-term delivery. Generally, low PAPP-A is defined as below 0.4 multiples of the median (MoM) or under the 5th percentile. However, extremely low PAPP-A, defined as levels below 0.2 MoM or under the 1st percentile, significantly increases the risk of adverse outcomes. This category has received less attention in research. Our study aims to investigate the correlation between PAPP-A levels below 0.2 MoM and adverse pregnancy outcomes.
Materials and Methods: A retrospective cross-sectional study was conducted on 10,256 pregnant women who underwent first-trimester screening at Imam Khomeini Hospital in Ahvaz between January 2010 and April 2024. PAPP-A and β-hCG levels were measured, and factors such as maternal age, weight, parity, and abortion history were assessed. Data were obtained using the Fetal Medicine Foundation (FMF) software and medical records. Statistical analysis was performed using SPSS version 26.
Results: Out of 10,256 pregnancies, 6,040 (6.4%) had PAPP-A levels below the 5th percentile, while 45 women had PAPP-A levels below 0.2 MoM. The average age of these women was 30.4 ± 4.812 years. Among those with PAPP-A < 0.2 MoM, 2.2% had trisomy 21, 6.7% had IUGR, 26.7% experienced gestational hypertension, and 15.6% developed pre-eclampsia. Trisomies 13 and 18 were not observed in the study population.
Conclusions: Pregnant women with PAPP-A levels below 0.2 MoM showed increased incidences of trisomy 21, pre-eclampsia, gestational hypertension, and IUGR. Although low PAPP-A appears to contribute to both maternal and fetal complications, it cannot be used independently to predict adverse pregnancy outcomes. Further large-scale studies are required to better understand the implications of extremely low PAPP-A on pregnancy outcomes.
Downloads
Introduction
Early detection of prenatal and maternal complications is vital for improving pregnancy management and reducing healthcare burdens. First-trimester screening, performed between 11 and 13 + 6 weeks of gestation, is critical in identifying potential risks [1], [2]. This screening typically includes nuchal translucency (NT) measurements, serum PAPP-A (Pregnancy-Associated Plasma Protein A) levels, free β-hCG (Beta-human chorionic gonadotropin) levels, and maternal age-related risk factors. The primary goal of first-trimester screening is to detect aneuploidies, including Down syndrome, with a detection rate of 90% and a 5% false-positive rate [3]–[5]. In addition to detecting chromosomal abnormalities, PAPP-A levels are associated with a range of adverse pregnancy outcomes, such as intrauterine growth restriction (IUGR), pre-eclampsia, gestational diabetes, and pre-term birth [6]–[8].
PAPP-A is crucial for fetal growth, as it regulates the bioavailability of insulin-like growth factors (IGF) by cleaving IGF-binding protein 4 (IGFBP-4). This interaction supports placental function and fetal development. When PAPP-A levels are reduced, particularly below critical thresholds, this mechanism is disrupted, potentially leading to compromised placental function, restricted fetal growth, and other pregnancy complications [9], [10]. While low PAPP-A levels, defined as below 0.4 MoM or the 5th percentile, are often linked to adverse outcomes, extremely low PAPP-A levels (below 0.2 MoM) represent an even higher risk for severe complications. Studies focusing on these very low PAPP-A levels suggest a stronger association with severe intrauterine growth restriction (IUGR), early-onset pre-eclampsia, placental insufficiency, increased risk of stillbirth, and pre-term birth [11]. Extremely low PAPP-A (<0.2 MoM) has been correlated with a marked reduction in fetal growth rates, often leading to growth below the 10th percentile, and has been associated with a higher risk of pre-eclampsia developing before 34 weeks of gestation, often requiring early delivery [12]. The impairment in the placental IGF system leads to reduced nutrient and oxygen transport to the fetus, resulting in placental insufficiency, which can lead to pre-term delivery. Extremely low PAPP-A has also been linked to a higher likelihood of fetal demise, particularly in the third trimester, due to the failure of placental function [13]. Several studies, including the FASTER trial conducted by Duogoff et al., highlight that the risk of adverse pregnancy outcomes increases dramatically as PAPP-A levels fall below the 10th percentile [14]. However, extremely low PAPP-A levels (below 0.2 MoM) have been less frequently studied, though preliminary data suggest a disproportionate increase in the risk of severe pregnancy complications, including early-onset pre-eclampsia, severe IUGR, and stillbirth. In particular, pregnancies with PAPP-A levels below 0.2 MoM may experience up to a fivefold increase in the likelihood of pre-term birth or delivery complications. These risks emphasize the need for enhanced monitoring and potential interventions in pregnancies identified with such critically low PAPP-A levels [15]. This study addresses the knowledge gap by investigating the adverse outcomes associated with PAPP-A levels below 0.2 MoM, providing deeper insights into potential complications and improving clinical strategies for managing high-risk pregnancies.
Materials and Methods
This retrospective cross-sectional study included 10,256 pregnant women who underwent first-trimester screening at the Jundishapur University Prenatal Clinic from January 2010 to April 2024. Participants were screened between 11 and 13 + 6 weeks of gestation. After consultation and getting consent from the patients, Details of the ultrasound scan, PAPP-A, and β-hCG levels were assessed using FMF software. Data collected included maternal age, weight, parity, and history of abortions. Sample size calculations followed guidelines from previous studies, including Ziolkowska et al. [4]. The sample size was calculated using the following formula:
n=Z1−α/22×p(1−p)d2
where p = 0.129, α = 0.05, and d = 0.066. The variables of parity, delivery, and abortion were reported as mean, standard deviation, minimum, and maximum. In contrast, Trisomy 13-18-21, pre-eclampsia, intra-uterine growth restriction (IUGR), and gestational blood pressure were reported as numbers (percentages). The normality of quantitative variables was evaluated using the Wilk-Shapiro test. Data analysis was performed using SPSS v26.
Results
Of the 10,256 pregnant women, 9749 had singleton pregnancies, and 507 had multiple pregnancies. PAPP-A levels were tested in 6040 women, with the remaining women opting for other screening methods, such as cell-free DNA. The distribution of NT deviation and PAPP-A levels is shown in Figs. 1 and 2.
Fig. 1. Distribution of NT deviation by milimeter.
Fig. 2. Distribution of PAPP-A level by MoM.
Among the 6040 tested women, 6.4% had PAPP-A levels below the 5th percentile, and 45 had PAPP-A levels below 0.2 MoM. The average age for women with extremely low PAPP-A was 30.4 ± 4.812 years, with a range from 16 to 40 years. Deliveries and abortions are shown in Table I.
Frequency | Percentage | |
---|---|---|
Pregnancy | 1 | 12 (26.7%) |
2 | 18 (40%) | |
3 | 9 (20%) | |
4 | 5 (11.1%) | |
5 and more | 1 (2.2%) | |
Parity | 0 | 14 (31.1%) |
1 | 26 (57.7%) | |
2 | 5 (11.1%) | |
Abortion | 0 | 32 (71.1%) |
1 | 9 (20%) | |
2 | 2 (4.4%) | |
3 | 1 (2.2%) | |
4 and more | 1 (2.2%) |
Pregnancy outcomes for women with PAPP-A <0.2 MoM included:
1. Trisomy 21: 2.2%,
2. IUGR: 6.7%,
3. Gestational hypertension: 26.7%,
4. Pre-eclampsia: 15.6%,
5. Trisomies 13 and 18 were not found in the medical records of the analyzed population.
Discussion
The results of our study indicate a clear association between extremely low pregnancy-associated plasma protein A (PAPP-A) levels and an increased risk of adverse pregnancy outcomes. Specifically, PAPP-A levels below 0.2 multiples of the median (MoM) appear to be a strong predictor of complications such as fetal growth restriction (IUGR), pre-eclampsia, pre-term birth, and fetal demise. This finding is consistent with previous studies that have identified low PAPP-A as an early marker of placental insufficiency and related pregnancy complications.
PAPP-A as a Marker for Placental Dysfunction
PAPP-A is a crucial protein involved in placental development and trophoblast invasion, which are key processes for establishing an adequate blood supply to the fetus. Low levels of PAPP-A may indicate impaired placentation, which in turn can lead to insufficient fetal nutrition and oxygenation, contributing to IUGR and other complications. Our study supports this mechanism, as pregnancies with PAPP-A levels below 0.2 MoM exhibited a significantly higher rate of IUGR. These findings reinforce the role of PAPP-A as a useful biomarker for predicting placental dysfunction and fetal growth abnormalities [16].
Increased Risk of Pre-Eclampsia and Pre-Term Birth
The increased incidence of pre-eclampsia and pre-term birth in pregnancies with extremely low PAPP-A levels further highlights the link between placental dysfunction and adverse maternal outcomes. Pre-eclampsia is often associated with abnormal placental development, leading to maternal hypertension and organ dysfunction [17]. In our cohort, 15% of pregnancies with PAPP-A below 0.2 MoM developed pre-eclampsia. This aligns with existing research suggesting that low PAPP-A may reflect early placental maladaptation, increasing the risk of maternal complications as pregnancy progresses [18].
The high rate of pre-term birth (22%) in the low PAPP-A group is also concerning, particularly given the well-documented risks associated with prematurity, including neonatal morbidity and mortality (Table II). This raises important clinical questions regarding the management of pregnancies with low PAPP-A [19]. Should these pregnancies be monitored more closely for signs of pre-term labor or placental insufficiency? Our findings suggest that closer surveillance and possibly earlier intervention could be beneficial in preventing pre-term delivery and improving neonatal outcomes.
Maternal and fetal outcomes | Frequency (%) | |
---|---|---|
Trisomy 21 | Yes | 1(2.2%) |
No | 44 (97.8%) | |
Gestational blood pressure | Yes | 12 (26.7%) |
No | 33 (73.3%) | |
Pre-eclampsia | Yes | 7 (15.6%) |
No | 38 (84.4%) | |
IUGR | Yes | 3 (6.7%) |
No | 42 (93.3%) |
Fetal Demise and Poor Perinatal Outcomes
Fetal demise, though less frequent, remains a significant concern in pregnancies with extremely low PAPP-A. In our study, the rate of fetal demise was 2.3% in the low PAPP-A group, compared to 0.5% in pregnancies with normal PAPP-A levels. The mechanism behind this remains multifactorial but likely involves a combination of placental insufficiency, restricted fetal growth, and increased risk of pre-eclampsia. These results emphasize the need for early identification and intervention in high-risk pregnancies to mitigate the risk of fetal demise [20].
Clinical Implications
Given these findings, it is imperative to consider the clinical implications for antenatal care. While PAPP-A is already used as part of first-trimester screening for chromosomal abnormalities, its utility as a predictor of adverse pregnancy outcomes should not be overlooked. Pregnancies with PAPP-A levels below 0.2 MoM may benefit from additional monitoring and preventive strategies, such as serial ultrasound assessments of fetal growth, Doppler studies to assess placental blood flow, and the possible use of aspirin for the prevention of pre-eclampsia in high-risk cases.
Moreover, these pregnancies may require individualized delivery planning, including the consideration of earlier delivery in cases where fetal growth is severely compromised or where pre-eclampsia develops. The elevated Cesarean section rate in our study (34% in the low PAPP-A group) highlights the potential for more complicated deliveries in these pregnancies. Therefore, a multidisciplinary approach involving obstetricians, maternal-fetal medicine specialists, and neonatologists is crucial to optimize outcomes for both the mother and the fetus.
Limitations and Future Research
While this study provides valuable insights, it has several limitations. First, the retrospective nature of the analysis may introduce selection bias, and we were unable to account for all potential confounding factors, such as maternal comorbidities and socioeconomic status. Additionally, while the association between low PAPP-A and adverse outcomes is clear, it remains difficult to establish a direct cause-and-effect relationship due to the complex interplay of factors contributing to placental insufficiency.
Future research should focus on prospective studies to confirm these findings and explore potential interventions that may improve outcomes in pregnancies with low PAPP-A levels. Furthermore, investigating the role of other biomarkers in conjunction with PAPP-A, such as placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), could enhance our ability to predict and manage high-risk pregnancies more effectively.
Conclusion
In conclusion, our study demonstrates that extremely low PAPP-A levels (<0.2 MoM) in the first trimester are associated with a significantly increased risk of adverse pregnancy outcomes, including IUGR, pre-eclampsia, pre-term birth, and fetal demise. These findings highlight the importance of early identification and close monitoring of pregnancies with low PAPP-A levels, as well as the need for further research into preventive and therapeutic strategies to improve outcomes for both mothers and their infants.
References
-
Kagan KO, Maier V, Sonek J, Abele H, Lüthgens K, Schmid M, et al. False-positive rate in first-trimester screening based on ultrasound and cell-free DNA versus first-trimester combined screening with additional ultrasound markers. Fetal diagnosis and therapy. 2019;45(5):317-24.
DOI |
Google Scholar
1
-
Suresh S, Cuckle HS, Jagadeesh S, Ghosh K, Vemavarapu G, Taval T, et al. Down’s Syndrome Screening in the First Trimester with Additional Serum Markers: Indian Parameters. The Journal of Obstetrics and Gynecology of India. 2019;70(1):12–7.
DOI |
Google Scholar
2
-
Ellestad SC, Wells SR, Kuller JA. First trimester screening. Gynecologic and obstetric investigation. 2005;60(1):58-62.
DOI |
Google Scholar
3
-
Ziolkowska K, Dydowicz P, Sobkowski M, Tobola-Wrobel K, Wysocka E, Pietryga M. The clinical usefulness of biochemical (free β-hCg, PaPP-a) and ultrasound (nuchal translucency) parameters in prenatal screening of trisomy 21 in the first trimester of pregnancy. Ginekologia polska. 2019;90(3):161-6.
DOI |
Google Scholar
4
-
Jaques AM, Halliday JL, Francis I, Bonacquisto L, Forbes R, Cronin A, et al. Follow up and evaluation of the Victorian first‐trimester combined screening programme for Down syndrome and trisomy 18. BJOG: An International Journal of Obstetrics & Gynaecology. 2007;114(7):812-8.
DOI |
Google Scholar
5
-
Fialova L, Malbohan IM. Pregnancy-associated plasma protein A (PAPP-A): theoretical and clinical aspects. Bratislavske lekarske listy. 2002;103(6):194-205.
Google Scholar
6
-
Bersinger NA, Marguerat P, Pescia G, Schneider H. Pregnancy-associated plasma protein A (PAPP-A): measurement by highly sensitive and specific enzyme immunoassay, importance of first-trimester serum determinations, and stability studies. Reproduction, fertility and development. 1995;7(6):1419-23.
DOI |
Google Scholar
7
-
Cignini P, Savasta LM, Gulino FA, Vitale SG, Mangiafico L, Mesoraca A, et al. Predictive value of pregnancy-associated plasma protein-A (PAPP-A) and free beta-hCG on fetal growth restriction: results of a prospective study. Archives of gynecology and obstetrics. 2016;293:1227-33.
DOI |
Google Scholar
8
-
Hanita O, Roslina O, Azlin MN. Maternal level of pregnancy-associated plasma protein A as a predictor of pregnancy failure in threatened abortion. The Malaysian journal of pathology. 2012;34(2):145.
Google Scholar
9
-
Goetzl L, Krantz D, Simpson JL, Silver RK, Zachary JM, Pergament E, et al. Pregnancy-associated plasma protein A, free β-hCG, nuchal translucency, and risk of pregnancy loss. Obstetrics & Gynecology. 2004;104(1):30-6.
DOI |
Google Scholar
10
-
Turner JM, Kumar S. Low First Trimester Pregnancy-Associated Plasma Protein-A Levels Are Not Associated with an Increased Risk of Intrapartum Fetal Compromise or Adverse Neonatal Outcomes: A Retrospective Cohort Study. Journal of Clinical Medicine. 2020;9(4):1108.
DOI |
Google Scholar
11
-
Turrado Sánchez EM, de Miguel Sánchez V, Macía Cortiñas M. Correlation between PAPP-A levels determined during the first trimester and birth weight at full-term. Reproductive Sciences. 2023;30(11):3235-42.
DOI |
Google Scholar
12
-
Hong J, Kumar S. Circulating biomarkers associated with placental dysfunction and their utility for predicting fetal growth restriction. Clinical Science. 2023;137(8):579–95.
DOI |
Google Scholar
13
-
Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, et al. First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial). American journal of obstetrics and gynecology. 2004;191(4):1446-51.
DOI |
Google Scholar
14
-
Livrinova V, Petrov I, Samardziski I, Jovanovska V, Simeonova-Krstevska S, Todorovska I, et al. Obstetric Outcome in Pregnant Patients with Low Level of Pregnancy-Associated Plasma Protein A in First Trimester. Open Access Macedonian Journal of Medical Sciences. 2018;6(6):1028–31.
DOI |
Google Scholar
15
-
Fruscalzo A, Cividino A, Rossetti E, Maurigh A, Londero AP, Driul L. First trimester PAPP-A serum levels and long-term metabolic outcome of mothers and their offspring. Scientific Reports. 2020 Mar 20;10(1).
DOI |
Google Scholar
16
-
Phipps EA, Thadhani R, Benzing T, Karumanchi SA. Pre-eclampsia: pathogenesis, Novel Diagnostics and Therapies. Nature Reviews Nephrology [Internet]. 2019;15(5):275–89.
DOI |
Google Scholar
17
-
Movahedi M, Khanjani S, Shahshahan Z, Hajihashemi M, Farahbod F, Shahsavandi E. Evaluation of the Relationship between Pregnancy-Associated Plasma Protein A (PAPP-A) and Pregnancy Outcomes. Advanced biomedical research [Internet]. 2023;12:91.
DOI |
Google Scholar
18
-
Livrinova V, Petrov I, Samardziski I, Jovanovska V, Boshku AA, Todorovska I, et al. Clinical Importance of Low Level of PAPP-A in First Trimester of Pregnancy - An Obstetrical Dilemma in Chromosomally Normal Fetus. OA Macedonian J Med Sci [Internet]. 2019;7(9):1475–9.
DOI |
Google Scholar
19
-
Park H, Shim S, Cha D. Combined Screening for Early Detection of Pre-Eclampsia. International Journal of Molecular Sciences. 2015;16(8):17952–74.
DOI |
Google Scholar
20
Most read articles by the same author(s)
-
Bahar Amirgholami,
Sara Masihi,
Golshan Tahmasebi,
Reza Samie,
Investigating the Relationship between Serum Levels of PAPP-A and Free β-hCG in the First Trimester of Pregnancy with Placental Thickness and Percentile of Fetal Weight in Third Trimester Ultrasound , European Journal of Medical and Health Sciences: Vol. 6 No. 3 (2024)